75 – Catatonia in Neurodevelopmental Conditions Like SYNGAP1

Joshua Ryan Smith, MD

Dr. Smith’s Bio

Dr. Smith is an Assistant Professor of Psychiatry and Behavioral Sciences at Vanderbilt University Medical Center and the Vanderbilt Kennedy Center. He is a graduate of the University of Mississippi School of Medicine. He pursued clinical training in adult psychiatry at the University of Virginia and child and adolescent psychiatry at Harvard Medical School, Mclean Hospital, and Massachusetts General Hospital. During his training, Dr. Smith obtained subspecialty training in consult-liaison psychiatry, neuromodulation, and autism spectrum disorders at the Massachusetts General Hospital Bressler Program for Autism Spectrum Disorders and Lurie Center. In 2021, he joined the faculty at Vanderbilt to grow and develop clinical and research services in child psychiatry and autism spectrum disorders.

Dr. Smith’s primary research interest is in bridging the gap between clinical trial research and clinical care. His specific areas of interest include use of transcranial magnetic stimulation in autism, catatonia in neurodevelopmental conditions, consult-liaison psychiatry in children’s hospitals, and electroconvulsive therapy. Dr. Smith serves as an ad hoc reviewer for many well known medical journals.


hello everyone and welcome to today’s webinar. My name is Olga Bothe and I’m a syngap parent and part of the team here at SynGAP Research Fund.
Our presentation today is catatonia and neurodevelopmental conditions like SYNGAP1.
I have the pleasure to introduce today’s speaker Dr Joshua Ryan Smith. Dr Smith is an assistant
professor of Psychiatry and Behavioral Sciences at Vanderbilt University Medical Center and the
Vanderbilt Kennedy Center. He is a graduate of the University of Mississippi school of medicine and
he pursued clinical training in adult psychiatry at the University of Virginia and Child and
Adolescent Psychiatry at Harvard Medical School McLean Hospital and Massachusetts General Hospital
during his training Dr Smith obtained excuse me subspecialty training in consult liaison
Psychiatry neuromodulation and autism spectrum disorders at the Massachusetts General Hospital Bressler program for autism spectrum disorders and Lurie Center in 2021 he joined the faculty
at Vanderbilt to grow and develop clinical and Research Services in child psychiatry and
autism spectrum disorders Dr Smith’s primary research interest is in bridging the gap
between clinical trial research and clinical care his specific areas of Interest include
use of transcranial magnetic stimulation and autism Catatonia in your developmental disorders
consult liaison psychiatry in children’s hospitals and electric convulsive therapy
Dr Smith serves as an ad hoc reviewer from many well-known medical journals
a recorded version of this webinar will be available on the SRF website under webinars on the family menu by the end of this presentation you will have the opportunity to get to answer
your questions we’d love to hear from you so please write your questions in the Q&A below
for those of you just joining us welcome and again our speakers Dr Joshua Ryan Smith and his presentation today is catatonia in your developmental conditions like syngap1. It’s now
my pleasure to turn things over to Dr Smith thank you Olga for that really very kind introduction
I’m going to try to share my screen which is always a a dicey move so give me one second
all right so uh thank you again my name is Joshua Smith I’m a professor of Psychiatry
and Behavioral Sciences I am in the Division of Child and Adolescent Psychiatry but I see folks from all across the life cycle I see our youngest patient we have in clinic is
four our oldest one is 31 so I kind of think of myself as sort of a life cycle a psychiatrist
so here are my disclosures my Clinic’s called the men Clinic and we have three industry-sponsored
clinical trials virosa Roche and axial all of them are looking at improving symptoms of
autism and I received no direct funding or salary support from those they mostly keep the lights on
so our learning objectives for today we’re going to review autism and this new sort of terminology
profound autism and the reason I’m doing that is that I think it’s really important for us to have some vocabulary particularly as we’re talking about syngap and symptoms associated
with syngap we’re going to discuss Catatonia as a diagnosis and treatment and autism and other
neurodevelopmental conditions we’ll talk about the current research as well as the research that we’re doing in our lab we’re going to explore possible connections between Catatonia
and syngap1 and discuss future directions and opportunities and I want to put the caveat to
that I have a video and a few slides of a young man who has hyperactive Catatonia from Phelan
McDermott syndrome which is another genetic abnormality that’s associated with hyperactive
Catatonia and autism and the the video is I think it’s really important I think it’s a
good educational opportunity and his family has given me the permission to use it but I’m afraid
it could be potentially triggering to some family members or parents who have had kids with similar
symptoms and so I wanted you to be aware and I’ll give plenty of warning before I start it
so let’s talk a little bit about autism intellectual disability and really disparity so you guys may or may not be aware but the Atlanta commission for autism was released in
2021 by Catherine Lord and colleagues and she introduced this term profound autism to the
literature there’s been some you know debate about whether this term is appropriate or
sort of the utility of it but really I do think it’s helpful in terms of easily communicating how
severe symptoms are for somebody who needs criteria for autism so let’s go over the
requirements for that diagnosis or the criteria so it needs to be somebody over the age of eight who has one of these uh meets one of these criteria so requiring 24-hour access to an
adult who can care for them likely for the rest of their lives being unable to live completely alone not being able to tend to basic daily adaptive needs having an IQ less than 50 or
having limited vertical ability and again I’m going to use this term pretty regularly today
so comorbid intellectual disability and autism is the actually the CDC just released in the past
month a report of the prevalence of profound autism after the term was introduced and they
think that it’s about 24 of people with Autism would meet criteria for profound autism this data
I’m giving you is a little bit dated in terms of comparing it to that but basically there’s speculation intellectual disability is present about 30 to 50 percent of autistic individuals
and it’s more often associated with autism for folks that also have co-morbid genetic abnormalities and it only makes up five to six percent of autism clinical research which is
always wild to me and it looks like inclusion is actually worsening over time and I know I’m kind
of preaching to the choir a little bit if you’ll forgive the metaphor but the systematic exclusion
of folks with genetic abnormalities significant sort of symptoms limited verbal ability I think really does lessen our understanding of autism broadly across the Spectrum and it also
leaves our most vulnerable folks without significant clinical research to assist with
their symptoms and improve their quality of life and so with profound autism there’s an increased
risk for externalizing behaviors particularly aggression and there’s also a risk of medical and psychiatric hospitalization and that’s in areas that have the ability to hospitalize these folks
a lot of places including Tennessee where where I am there’s not a designated hospital for folks
with this particular sort of symptom profile the closest one is actually in Atlanta uh it’s called Laurel Heights and so if we have people to come in and they absolutely need hospitalization
for Behavior secondary to profound autism we oftentimes have to transport them there
so let’s talk a little bit about aggression and irritability in our developmental disorders oftentimes aggression and irritability is attributed to behavioral issues someone’s
attention seeking someone you know is trying to get something out of their behaviors and when that
happens it sometimes clouds our vision around is there something identifiable and treatable
that’s causing the aggression that we may be able to identify and treat and it also leaves us not
categorizing subtypes of aggression so there’s different kinds of aggression there’s aggression
that is self-injurious there’s aggression that’s injury to others there is aggression that seems
to be targeted there’s aggression that’s not targeted and identifying those and separating them out is really important because it allows us to say hey this is more likely X Y or Z that
we may be able to treat and then Catatonia is an area of particular interest to me clinically
and from a research perspective because it is something that results in aggression and irritability in neurodevelopmental disorders but it’s treatable identifiable and relatively
rapid in the response to treatment and we’re going to talk a little bit more about that
So what is catatonia? Catatonia is this is a little bit jargony so I’m going to say it
then we’ll break it down it’s a psychomotor syndrome with affective domains and distinct physical examination findings and what that means is that when I say psychomotor I mean
that people either have really increased amounts of motor activity early suppressed amounts of motor activity and affective domains excuse me is indicative of changes in one’s mood
sort of rapidly in responses to stressors or or not and classically this has been identified in
schizophrenia affective disorders meaning bipolar or bipolar depression Romania as
well as major depressive disorder or medical illness and typically when people think of
Catatonia they think of the stuporous iteration of Catatonia and we’ll talk about that a little bit in a more in a minute but the super iteration of Catatonia is when someone has posturing where
they’re unable to move their arms or they’re unable to follow commands they don’t eat or drink and they have periods of staring or they can’t it seems like they can’t move their eyes
to be able to identify who’s in the room with them or trying to speak to them and that that does happen in neurodevelopmental conditions you can certainly have the stuporous iteration
of Catatonia but a really pivotal paper in 2020 by vicares of serrano and colleagues found that 20.2
percent of autistic individuals have some degree of catatonic symptomatology they’ve experienced over the course of their life and 10 of autistic individuals may meet full criteria for Catatonia
and what’s interesting about that is that people with Autism and as we’re learning more autism and
additional neurodevelopmental disorders are more likely to have a hyperactive version of Catatonia
rather than a stuporous iteration of Catatonia so what vicares of Toronto found in his paper is that
the most common symptoms of catatonin autism were a loss of previously acquired verbal skills a lack
of cooperation or negativism that to my mind as a clinician could oftentimes be attributed
to oppositionality or attention-seeking behavior and then agitation and aggression
so there’s two versions again there’s the hyperactive version extreme agitation it’s less often diagnosed and it’s perhaps more common in autism than other neurodevelopmental conditions
and there’s a stuporous iteration which is generally considered the classical version and then from a psychomotor perspective some have actually characterized Catatonia as similar to
parkinsonism not in that it’s neurodegenerative but in that in Parkinson’s you can have both
symptoms of extreme motor activity hyper motor activity and also stuporous activity
and I think it’s important to mention here and we’ll reiterate it again is that Catatonia is
a lot like fever Catatonia always comes from something else and it’s a it’s a symptom that
we’re able to treat in the same way that you would give ibuprofen to lower fever you can
treat Catatonia in a similar sort of way but what causes Catatonia would be again sort of
like classically we think of schizophrenia we think of mood disorders medical conditions but
we’re finding out is that that autism and then other genetic conditions can be the sort of underlying cause of Catatonia particularly when stress is involved
so what does this have to do with syngap1? so for SYNGAP1, looking at the literature
myself is there’s a lot of characterization of challenging behaviors in SYNGAP1 and if
you really break it down the challenging behaviors line up considerably with Catatonia so affective
instability oppositionality or negativism Ataxia which you can also see in Catatonia
and then her current self-injury and aggression and while there have been reports investigating
Catatonia and other neurodevelopmental conditions there are no reports in the literature looking at this catatonin occurrence and GAP and we’ll talk a little bit more about that in a moment
but by the end of this I’m hoping to convince you that this may be something that occurs in syngap that we’re able to identify and treat
so this is the video that I was referencing I’m going to try to see if I can get it to play and again I want to just caution anyone that this may be someone distressing for folks to
watch but I also want you to know too I’m going to go ahead and skip a slide that this young man is name is Lucas is doing much better this is Lucas and I he’s walking in to actually get ECT
he’s doing much much better has had a really positive outcome so I want to make sure that
I’ve sort of introduced that before I show you this video of some more challenging symptoms
so you hear him kind of making these vocalizing sounds that sound distressed and in Catatonia
work we call this veration where it’s the production of sort of nonsensical sounds
oftentimes in a repetitive manner which can be distressing and you can see that he’s moving chairs around this is again sort of like a in Catatonia we call this manneristic behaviors I
always tell the trainees that mannerisms are anything that you see someone doing and you’re like why are you doing that it seems very odd and he certainly has that
and mannerisms can progress to where they are aggressive in nature or self-injurious
so I want to take a moment here to show you that he is posturing right so when I was describing
the more stuporous version of Catatonia we were talking about the fact that posturing occurs posturing occurs in hyperactive Catatonia as well so you can see that he takes a a brief minute
maybe even less than a minute for this posture focused and he’s also having some diminished eye
contact from his Baseline when you’re treating folks with neurodevelopmental conditions with Catatonia it’s key to know their Baseline to collaborate with families and to make sure that
you understand where families are hoping that their their child or their you know their Ward
will get back to what what symptoms you’re hoping the will improve hey bud what’s wrong Twitter
he’s posturing there again foreign and he’s also having this kind of families often describe it
as this look of knowing that aggression is about to come so he’s about to have an aggressive episode the family member filming this was not harmed you want to watch a movie
Paw Patrol
we can watch Paw Patrol
and so again I know that can be a distressing video to watch it’s honestly distressing for me to watch but he’s doing much much better now has responded beautifully to treatment
that is me for what it’s worth next to Luke so
the symptoms of Catatonia are wide-ranging and I think that’s important to acknowledge because
a lot of times I’ll start introducing catatonic symptoms to families and they’re like well this is a lot of symptoms that you’re describing and it’s true and in fact there’s actually a lot of
symptom crossover between Catatonia and autism and other neurodevelopmental conditions and so
when we’re looking at this this is an excellent graph that’s from this paper structural neural
mechanisms of Catatonia by Sebastian Walther and Dr heckers who’s our chair here at Vanderbilt is the senior author on this paper there’s increased psychomotor activity agitation excitement
impulsivity combativeness and then decrease stupor Ambit tendency which is where folks are stuck in a
movement so they’re sort of repeating the movement over and over again or another great example there’s an excellent book if anyone’s interested in Reading further called autistic breakdown it’s
written by Dr Shaw in the UK she describes about 20 or 30 cases of Catatonia and autism
and she often describes a tendency as being stuck sort of entering a room or crossing a threshold
and then rejiberation we’ve discussed echopraxia and echolalia echopraxia is repeated movements like observing somebody and then having the movement occur and
then echolalia is repetition of a word that’s spoken automatic obedience is an inability to
I appreciate the not in a command so oftentimes I’ll tell folks I’m assessing shake my hand
they’ll shake it and I’ll say please do not shake my hand and they’ll continue to shake it despite my sort of I’m sorry I’m having a difficult time with my mouse here despite my
efforts to get them to not do that and then there are other terminology and Gigan Halton are German
terms that are carried over from when Catatonia was first described in Germany in the 1800s
Gigan Halton is when you can lightly or Gigan Holton is also called peritonia it’s when you get equal and opposite resistance in terms of like looking at someone’s muscular pressure as
you’re pushing against their arm and then Gigan Halton is actually folks will have a light tap of their arm and they’ll drift it in the air like this and then continue to hold it and then grass
reflex is not what we traditionally think of grass reflex so grass reflects in sort of like
neonatal sciences that you rub the inside of a baby’s hand and they will hold your thumb
as you rub it because grasp reflexes reaching out for everything nearby and trying to grab it
so there’s a lot of diagnostic skills we use in Catatonia work there’s the bush Francis Catatonia rating scale Which is far in a way the most often utilized
it is validated in neurotypical folks with psychiatric conditions but it’s lacking in
Pediatric and neurodevelopmental data there’s also the Pediatric Catatonia rating scale which is 20
Questions 14 actually are from the bush Francis itself and then six additional symptoms excuse me
and this was put together by Dr Cohen and colleagues in in France and they do
outstanding research and I’ll actually show you one of their papers here in a moment but they also identified acrocyanosis which is uh really cold extremities schizophasia which is
basically sort of like the production of garbled speech in an automatic compulsive movements
and the scale that we use most commonly is the canner Catatonia rating scale so it includes a
severity measure and an examination it’s more precise but it still misses some specific
pediatric symptoms so I’ll just generally ask about those it’s not validated but it is designed
for neurodevelopmental disorders and so on our service we will treat I have an outpatient clinic
where I see folks with Catatonia but I also see a lot of Catatonia at the Children’s Hospital here
and what we do is we end up using a combination of the Bush Francis and the canner Catatonia rating scale and by using a combination of those we oftentimes will catch everything we need to
so just some more kind of highlights about Catatonia it’s more prevalent in biologically male individuals if it’s Pediatric and onset it usually occurs around puberty
the DSM-5 you only need three of the 12 symptoms to make the diagnosis and that’s
that’s really to sort of encourage clinicians to think about Catatonia when symptoms are occurring and then regressive symptoms are more common in children and that’ll also include and
just folks within your developmental condition when I say regressive symptoms I mean loss of a previously acquired skill urinary incontinence social withdrawal and reduced eating and drinking
and then again more externalizing behaviors like aggression self-injury and it comes from something
so it’s similar to fever and it’s likely due to this is a little jargony but I’ll I’ll Circle back on it so it’s likely due to dysfunctional gabaergic endocrinergic signaling and what that
means is that it’s likely secondary to the brain being too excitable to hyper excitable
and potentially hyperplastic and we’ll talk about how that likely pertains to sync app one shortly and it’s also very likely that symptoms of Catatonia may be worse in by antipsychotics I
wish I had a nickel for every family that’s told me that their child’s symptoms were worsened by antipsychotic so they were started on risperidone or proposal or something like that and
the aggression actually worsen and that’s always something for me that you know raises a red flag
so we’ve talked about this but just to reiterate Catatonia known psychiatric causes major depressive disorder bipolar schizophrenia delirium can also cause
Catatonia and I’m happy to discuss that in more detail if anyone’s interested and the neurodevelopmental conditions it’s been described in autism feeling McDermott syndrome
like Lucas that we saw previously trisomy 21 Prater Willy juvenile Huntington’s and others
so there’s infectious causes as well there’s meningitis you can also get electrolyte derangements meaning like low levels of sodium low levels of potassium
encephalites uh infectious Encephalitis but also autoimmune and then status epilepticus
seizures can actually precipitate Catatonia as well which is certainly something to be
concerned about in syngap given the you know really high prevalence of early onset
epilepsy neuroleptic malignant syndrome is a very hotly contested Topic in psychiatric
literature there’s a lot of people that say that neuroleptic malignant syndrome is a worsening of Catatonia if you give someone antipsychotic but we have described it it looks a lot like
Catatonia into treatment is the same and it happens after receiving an anesthetic
so this is a fantastic paper by Scott Beach and colleagues came out in 2017. and it is the Far
and Away the most robust review of treatment of Catatonia and this is again for neurotypical folks
with psychiatric conditions or medical illness and it’s for adults so this paper looks at adults so
you start with IV Lorazepam Ivy Ativan you get something called an Ativan challenge so in an
ideal Universe we would see someone with Catatonia likely in the hospital setting we would treat
them with Ativan about two milligrams IV and then literally within about 10 to 15 minutes we would see symptom Improvement and that’s actually our diagnostic criteria which is are they responding
to Ativan is it improving their symptoms in a 10 to 15 minute time frame and if it does then you
have your diagnosis you know it’s Catatonia you know what to do next and neurodevelopmental work
this is more complicated and we’ll talk about that in a moment and then ECT is usually the next treatment because Catatonia can be really debilitating and sometimes life-threatening ECT
is I’m also an ECT provider at Vanderbilt and I’m a big proponent of ECT ECT is heavily legislated
particularly in Tennessee and in California and we’ll talk about that in a minute as well and so it’s hard to get treatment for children and they can be hard to get treatment for adults that
need someone to consent for them and then a glutamate antagonist which is either romantine
or mantidine and then anti-seizure medications and then antipsychotics and what I end up doing
is I go here so I start with a benzodiazepine I oftentimes will use a longer acting benzodiazepine
because we’ve had more success using longer acting benzodiazepines like diazepam or clonazepam
relative to lorazepam and then I will move to glutamine antagonist momentine is a medication I
use really frequently the trainees here actually tease me about how often I use it but it’s very it’s very safe it’s also used off label for irritability and autism and off label for ADHD the
side effect profile is generally just GI distress there’s also a slightly elevated risk of seizure
but if I’m also giving somebody a benzodiazepine my concern for precipitating a seizure is lower
and then anti-epile Optics from there valproic acid is the one with the most amount of evidence
valproic acid we always need to be cautious with using it for anyone that has a uterus
because it’s a traged meaning that if there’s a fetus it can be really devastating to the fetus
and I would say too I it’s I have to get a long way before I consider doing antipsychotics and
the reason being is that a lot of the folks that I work with they’re exquisitely sensitive
to antipsychotics and a lot of that is because I think we don’t really understand the connection
between Catatonia and neurodevelopmental disorders well enough to say these three antipsychotics which have good evidence for their use in an adult neurotypical folks with Catatonia
that it will definitively work if I go for them I’ll usually use low potency antipsychotics
Quetiapine olanzapine clozapine is the one that has the best evidence for treatment of
Catatonia but that’s a whole other sort of issue because you have to get weekly blood draws to get
clozapine because it can suppress white blood cell activity and potentially cause infection the risk of that is really low but that’s sort of the system that we’re in and unfortunately
I think it’s under prescribed because of that and I don’t really know if weekly blood draws are absolutely necessary for that but that’s the that’s the situation we have there
so we talked about this a little bit we classically use the laureza Pim challenge to diagnose Catatonia one to two milligrams of IV larazepam dosing is typically three to four times
a day IV formulation is most often utilized particularly in the hospital and reduced oral
intake is a Hallmark symptom of Catatonia so you really need to use IV in particular cases where
that’s a primary symptom and then you need to Escalade doses quickly to avoid malignant Catatonia which we’ll talk about in a moment and then transitioning to oral in about two days so
again that’s a very idealized version of what can happen in Catatonia in autistic Catatonia and in
Catatonia with other neurodevelopmental conditions we have found in our clinic and I’m going to show you guys some some pretty significant data on this is that the longer acting medications tend
to work better for children and for folks with neurodevelopmental conditions particularly autism or symptoms of autism and part of that we believe is that autism based on a lot of the neuroimaging
research and as well as TMS research which tests for improbes for how hyperactive the cortex is
has shown that the cortex is likely hyperplastic and what that means is that the cortex the brain
of somebody with autism rapidly acclimates to whatever you introduce to the system so if you give someone a short acting medication like Lorazepam they may not have a the response you
would expect a neurotypical person to and so our hypothesis is that we need higher doses of longer
acting benzodiazepines to get similar sorts of success in terms of treating Catatonia for folks
with autism and neurodevelopmental conditions and again I’ll share that data with you shortly
so if you’ll forgive me my soapbox for a minute ECT is a very safe and often life-saving
intervention we released a paper in the Journal of autism and developmental disorders here where we did a 10-year retrospective analysis of everybody with autism with or without intellectual
disability who received ECT about 90 to 95 percent of folks had statistically significant clinical
improvements in a myriad of different symptoms psychosis Catatonia irritability aggression
it’s really effective and it can be a life-saving treatment I mentioned malignant Catatonia earlier
mining Catatonia is something we are concerned about it’s when Catatonia results in Vital sign
changes so elevated heart rate elevated blood pressure and when that’s happening we really need to look at using ECT because if malignant Catatonia goes untreated it has a mortality rate
about 10 to 20 percent again in neurotypical populations but it can be a medical emergency
and Tennessee in California are two of the most restrictive States for ECT care so in Tennessee
anyone under the age of 14 you have to have two psychiatrists agree that ECT has indicated one
of them cannot charge for the consultations so they can’t stand to gain anything financially then you have to have a group of seven people from different Specialties agree that ECT has indicated
then you have to go before a judge and generally the state of Tennessee will assign the child a
guardian ad litem will assign there’ll be legal representation from the hospital and then the
state will have their own lawyer and the three of them come as well as the family generally because the the child is not able to come or the patient and the judge will sign off I’ve done this a few
times I’ve never had a judge say no and there is a caveat in the Tennessee laws around ECT that say
that there’s absolutely emergency you can go ahead and do it but what’s tricky is that if someone comes into the hospital and they have malignant Catatonia I’m going to treat them with really
large dose benzodiazepines maybe even have them in the ICU on an infusion of benzodiazepines and so
it becomes a question of what is an emergency so if you stabilize somebody with benzodiazepines in
like in ICU is it still an emergency and legally at that point it’s probably not because it has
to be an absolute life-threatening situation California is even more restrictive so anyone under the age of 16 usually just can’t get ECT and it’s been so significant enough that folks
have had to be transported out of California to either Utah or Nevada to receive treatment
and this is a great paper that outlines some of the state restrictions if you’re interested there
and so this is a quick case of a child that we took care of with childhood onset schizophrenia
she presented with catatonic symptoms there was a delay due to the ECT legislation where we had to
arrange everything to go before a judge and these are days these little ticks here and essentially the child did not eat for this many days until they were able to receive ECT treatment
here and if we were able to start earlier the morbidity would have likely been introduced
so again momentum Anthony really safe medications robust safety profile when adults and children
momentine will use doses of 20 milligrams to 40 milligrams a day my 19 can go as high as 400 milligrams daily
and as uh I said there’s a slight risk of seizures momentine is cleaner meaning
it is less sort of receptor profiles and whatnot and it has a lower risk of seizures
relative to a mantidine and then we talked about that it’s a kind of medication sorry
so what happens if we treat quickly um ideally we’re able to confirm the diagnosis of Catatonia
and have people improve and sooner is better because Catatonia acts a whole lot like seizures
and you you all may know that like seizures that go untreated are more likely to happen again more likely more be more severe and so I’m a big proponent of trying to be as aggressive with the
treatment as we possibly can until resolution of symptoms and oftentimes that means having really
dose high-dose benzodiazepines and this requires a degree of you know trust certainly with the family
the patient’s family sometimes the patient around look we’re doing really high dose benzodiazepines
that means that we need to be really careful about sedation so sedation starts happening that means
that our dose is too high and just doing a lot of Education around that with families and then
you know the risk of going untreated would be poor oral intake failure to thrive potential for
refeeding syndrome and then malignant Catatonia as well and I want to reiterate too it’s really
important to identify if there’s an underlying cause and if that cause is treatable so I’ve already said that autism genetic conditions can cause Catatonia but also too folks with autism
and genetic conditions can get medical illnesses which cause Catatonia and so we need to make sure there’s no sort of symptoms that are happening um that we may think are medical conditions causing
the Catatonia even if we can say okay it’s autism or you know it’s feeling McDermott syndrome and so we think it’s from that uh we need to still make sure they don’t have you know a fever or
Encephalitis or other sort of metabolic changes and so oftentimes we’ll get an EEG get Labs
um and if there’s concern for autoimmune Encephalitis Vanderbilt Children’s Hospital has a great clinical pathway that you can access with this QR code but really we need more research
so what’s next and what are we seeing so I’m excited to show you some of our data but I will
say that um we don’t have data for this yet but the the report from all over the country in the world is that there’s Rising rates of Catatonia and we really don’t know why we we think that
it’s probably improved identification we’re using better scales we’re more aware of it but also too
there’s a question of is covid contributing covids and neuroinflammatory virus when people got that
did they increase their risk for Catatonia or did they go ahead and have Catatonia if they were potentially going to have it later in life we really don’t know as well as sort of the stress
that Catatonia put on a socially in terms of isolation um there’s there’s a lot to to learn and
uncover there so I’m excited to share some of our data with you so this is from our clinic so again
um the men Clinic is we have a clinical trial arm and then we have a longitudinal treatment arm
and in that longitudinal treatment arm we have 33 folks with catatonia so uh biological sex distributions about 50 50 almost the average age of folks that we have are
16 years the minimum is five maximum is 31. and the vast majority of our patients with Catatonia
have a diagnosis of profound autism and then this would be intellectual disability disorder next
childhood schizophrenia next and then autism without intellectual disability we actually have three cases of seronegative autoimmune Encephalitis um which basically means that they
have autoimmune Encephalitis with the antibody that can be identified and they’re usually from racial or ethnic groups that are generally excluded from Clinical Research black folks
um folks of agent here at Heritage that are not included in antibody research to identify
encephalitis and then we’ve also had a young man who has um who contracted influenza and developed Catatonia he’s doing he’s doing really well
so these are the presenting symptoms and again I want you to think about syngap in terms of
challenging behaviors that have been described in literature so um there’s aggression as the primary
symptoms 74-33 and again these some of these folks come in with more self-injury is 20 or 33 and then
stupor is 18 of 33. and um Jackie has given me permission to share her daughter Jaden is one of
our patients and she’s our uh only patient with syngap1 who has hyperactive Catatonia and I’ll
show you a graph that represents her treatment and hopefully we’ll be able to write up her case and sort of share with other folks that Catatonia is something that should be considered so these
are the other genetic conditions there’s the George syndrome 22q11 Down syndrome Trisomy 10
neuro Beach invariance Gaber and Rhett syndrome and about 30 percent of our patients have been
treated with ECT and I’m really proud of this number here so we’ve been able to significantly
reduce admissions to inpatient psychiatric inpatient medical admissions so there’s not
really any good data that says like hey this is the this is how often people with Catatonia are readmitted but there’s a huge study that looked at childhood psychosis and I thought comparing it
to that would be probably comparable and the rate of readmission for childhood psychosis is about 40 in a calendar year we’ve been around for two years and we’ve only had 18 of our patients get admitted
foreign so I’m going to share with you uh some of our really research I’m super proud of and really
happy to work with a lot of amazing folks so all of our research that’s currently under review or
has been published is includes only kids and we’re going to publish on Catatonia treatment in adults
with neurodevelopmental conditions in the very near future we’re just continuing to collect data there and so the next few tables and graphs I’m going to show you they’re currently under
review with the frontiers of child adolescent Psychiatry it’s also continuation of this brief report where we characterized hyperactive catatonin and profound autism that we saw at
the Children’s Hospital and every patient that we’ll talk about was treated with at least the benzodiazepine and that’s important to consider when you look at our tables here in a moment
so this is from our study this is not from the clinic itself and this also includes folks that are not in our Clinic that we weren’t able to follow and so we had um 60 biologically male 40
biologically female the mean age was 13 and a half and these are our ethnicity distributions
and something I’ll point out to you is that I know in the sungap community there’s a lot of concerns
around like psychiatric medications or there’s a lot of polypharmacy there’s a lot of medications that are being used and in this particular study we found that 24 of the 31 folks had previously
been on a psychiatric medication the range of that was we have kids that have been on up to 12 to 13 psychiatric medications without clinical Improvement and I think our mean was six or seven
uh medication trials and then 26 of the 31 had a comorbid neurodevelopmental diagnosis and I
think that’s really important to to highlight as well a little bit of his selection bias because we’re a Vanderbilt Children’s Hospital and so we’re oftentimes going to see folks with really
significant neurodevelopmental conditions and so there’s a little bit of selection bias there but I think it’s an important distinction and then 10 of the 31 have history of seizures
which we’ve talked about there’s there’s certainly a connection between epilepsy and catatonia
so again to highlight the challenges around dosing so what we’ve seen is that Folks at
Catatonia really need high-dose benzodiazepines to have clinical response and in this particular
study we found that the mean um amount of Klonopin in a single day that someone needed
for stabilization a child was seven milligrams and for diazepam which we used in four of the
31 cases it was 160 milligrams and they give you a point of reference that’s a mean of about 14
to 28 milligrams of Lorazepam which is that’s the mean it’s a lot and it’s it’s an issue of comfort
it’s an issue of communicating with families about the fact that we need high doses and it’s
also a comfort with folks in the community so if we have people that come into children’s or
come into the psychiatric hospital they need high doses of benzodiazepines and we’re trying to find them an outpatient provider it can oftentimes be really challenging to find an outpatient
provider who’s comfortable with that amount of benzodiazepine and then these are the other
medications that were represented we discussed these already but momentine was used in 12 of 31 mantidine and one vaporic acid and four of the 31 kids and then um Trileptal Abilify and close p
so this is just to show you that we assessed all of these kids by four different measures so we
used the bush Francis Catatonia rating scale we use the canner severity scale and the canner this
actually should say canner examination sorry about that and all three of these showed what this means
is that they all had statistically significant reductions in their symptom profile and to make
sure that we weren’t just sort of looking at the numbers in a in a way that was like don’t look at everything’s going well we had uh four of our authors go back and review all the charts and
assign a number something called the cgii so basically the cgii is a scale of one to seven
one and two are considered significant improvements three is minor Improvement
four is no improvement and then numbers below four are considered worsening and so we had four of our authors go back look at um look at the charts and then assign a number
of clinical Improvement so the probability of scoring a two or less so again statistically significant Improvement was 0.86 and then 98 of the patients that we saw scored a three or less
and that was across four uh authors and we were blinded to um the results of the other authors
and this is a really interesting table so everybody was on a benzodiazepine either clonazepam or dies fam and so 10 of them um only needed benzos and then 18 of them needed
a benzodiazepine plus an additional medication usually a glutamate antagonist like marmantine or amantanine and then for folks that needed benzo plus two it was um because of two this is
a little bit confusing sort of Distinction here was two patients that needed more
and this is just a box and whiskers plot to show you what we already talked about so this is the bush Francis Catatonia rating scale this is when we met folks and this is a little challenging too
um and I’ll share Jaden’s uh clinical improvements with you all and this is an important distinction
when you look at that chart too is that folks with autism or neurodevelopmental condition are
going to have an elevated Bush Francis Catatonia rating scale all the time because there’s a lot of
symptom crossover between Catatonia and autism or catatonian or developmental conditions and so what we’re looking for is are we getting back to the number where that is where they
live that’s their Baseline number as opposed to um looking at it to go completely to zero
because these are not designed to go to zero for folks with neurodevelopmental conditions and so when I say Baseline here too I mean like when we encountered the patient with
um Catatonia and so the average score was close to 20 here and then at stabilization the average scores of five and this goes to uh 68 total the canner severity goes to 144. the average
was a little above 35 for when we met Folks at Catatonia and then the score at stabilization
was a little below 10 and then the Candor exam is out of 12 and again when we met folks there’s
a really big outlier here but generally it was three and then zero was the average for the exam
so this is interesting stuff but what does it have to do with sync app why am I talking
to you guys so sync app one mutations likely result in complications due to the brain being
too excitable or the brain being too plastic and evidence for that includes the fact that same Gap
1 folks have a lot of symptoms consistent with autism which we have already sort of established is there the prevailing theory behind autism is that it’s secondary to the brain being too
excitable or too plastic and then early onset epilepsy is another additional sort of like
evidence for the fact that the brain is probably too excitable intellectual disability in ataxia and similar to syngap it’s been hypothesized that Catatonia is due to reduce inhibitory
tone in the brain and while there’s no published reports the same Gap there are many in other neurodevelopmental conditions and as we talked about Jaden
um will likely be the the first patient that’s described to uh experience hyperactive catatonia
and so just to go back to the slide that we discussed at the beginning what does this have to do with sync app so again published reports of challenging behaviors in syngap
really cover a lot of symptoms that are consistent with catatonian autism
affective instability oppositionality Ataxia or current self-injury but this is an area
of untapped research in the syngap that I think is you know certainly a promising one
so with Jackie’s uh permission this is um this is Jaden’s sort of clinical profile so these
are the number of visits that I uh where I saw Jayden and I met her and she actually was not
having catatonic symptoms at the time I met her she established care um Jackie and Jaden were looking for a psychiatrist who treated folks in our developmental conditions and
then in our third appointment she started developing symptoms of Catatonia here and Jackie did an amazing job describing like Jaden’s history of having these surges of
challenging behaviors that would dissipate over time which fits the bill for sort of a recurrent Catatonia picture and we slowly went up on clonazepam and again I’ll kind of reiterate why
clinazepam over larizepam so these are the blue uh graphs here where you can see the dose and then we
started my Mantine as well and so as we went up uh Jaden’s symptoms improved and she was doing
really really well here and then unfortunately had another bump in her symptoms and so we’ve increased her clinius Pam some more and her score actually at our appointment yesterday is back down
here to 28 where um she had her period of greatest stabilization and I only used the canner severity
scale because a lot of our appointments were for telemedicine and it was difficult for me to do
um you know I can watch her and then I can have Jackie do some of the examination but I want to make sure I was giving you guys fresh data and so this is um just the severity skill
so just some additional thoughts previous work in autism has suggested that cortical hyperplasticity
and Hyper excitability may play a role in some development but what that means is that you have a
brain that rapidly acclimates so plasticity means that the brain can rapidly acclimate to what’s
around it or there’s actually this developmental level of plasticity where kids are learning things really quickly and so their brain needs to change really quickly and so we actually think there’s
probably a developmentally expected degree of hyperplasticity in kids which might make longer
acting medications more appropriate if children are experiencing Catatonia but also of folks with autism are experiencing catatonia and so again uh this is probably this is possibly a similar
issue in syngap based on what we know about send gaps or neurobiology and then hyperplastic and
hyperextailable brain May rapidly acclimate to new medications introduced to the cortex which may contribute to medication resistance which I know has been described in singap literature
and of course with like parent groups and this would explain why Lorazepam is not as effective
as we would hope that it would be when you’re treating someone who has like schizophrenia but otherwise has neurotypical development and it offers a possible explanation for that
so some big take-home points Catatonia is an identifiable and treatable condition that commonly occurs in profound autism and other neurodevelopmental conditions
a lack of familiarity with the condition assessment measures and discomfort with high-dose medications and or ECT likely leads to under recognition and treatment for other
providers like when I’m communicating with a pediatrician or a family medicine doc or really anybody outside of Psychiatry and even some folks in Psychiatry it’s a little weird
to talk about Catatonia because you you diagnose Catatonia based on your physical examination and despite us describing Catatonia in the 1800s we don’t have a biomarker for captonian like
there’s not a lab we can draw that says this is definitely what this is and so there’s Reliance entirely on the physical examination to guide treatment and honestly in modern medicine it’s
kind of odd like we have a lot of neuroimaging we have MRI like we’ve had these huge advancements the Catatonia is one of these things that still is like okay we don’t have anything
that we could definitively say like this is the biomarker so there’s a lot of Reliance on
um clinician opinion clinician examination to guide treatment and given the high degree of
connection between catatonin cortical excitability it’s likely that individuals to Singaporean have likely experienced Catatonia certainly Jaden has experienced hyperatica could the hybrid
catatonias responded well and while this hasn’t been addressed in literature we’re working on it
there are probably like more than 100 references um I was I’m happy to provide
them on a request and they’re also some are included in the slide deck as well
and these are my acknowledgments I really want to thank Jackie and um and Jaden for you know working with me it’s been a pleasure to have them in clinic and I
also want to thank all of our other patients and families uh as well as the bresler clinic where I trained and then the men Clinic where I currently am happy to take any questions and I’ll
leave the slides up if there are questions that are specific to slides we can go back to those
oh that was so good okay let me see I think Olga you could just read it if you want your question
if you’re here I am here yes okay I’m just curious I I had seen on one of the slides that you had
mentioned excuse me TMS what is the difference between ECT and TMS and is TMS something that
is considered as a treatment yeah Catatonia or neurodevelopmental ASD that’s a great question
so ECT is a is a much more invasive procedure but it has much more evidence for its use in
Catatonia and irritability and self-injury and autism um ECT is folks go to received CT they
are put under generalized anesthesia and their muscles are paralyzed and a seizure is induced and so really you just see a seizure occurring on the EEG and some light muscle fasciculations and
uh the time courses is shorter in ECT than it usually isn’t TMS TMS is non-invasive we use a
big magnet basically to inhibit or stimulate a certain part of the brain and part of our
research is looking at can we use TMs to develop biomarkers for Catatonia and autism and can we
use TMs to treat catatonin autism or potentially improve verbal ability for folks that have reduced
verbal ability with autism and so they’re they’re both neuromodulation in that they
both use electric currents to change the cortex but TMS is much more targeted and doesn’t require
generalized anesthesia but does require people to come like every five like five days a week
for six weeks to receive treatment and there’s not definitive literature that it helps with Catatonia yet whereas ECT is a little bit shorter in time course and has a lot more evidence for um
okay thank you nurse so ecd is like the last resort after medications don’t don’t work is
that correct yeah I think that um we probably don’t use it early enough um it is a really
really effective treatment in Catatonia but yes generally and totally understandably what parents want to do is we’ll try meds and then we’ll do ezt which makes perfect sense to me like if we’re my
child I would totally agree like you don’t want to have to go undergo an invasive procedure when you can just take medication to improve symptoms makes perfect sense um so generally that ends up
being the steps that we take sort of like when we are working collaboration with families okay
a lot of our kiddos and I know I’m jumping in with more questions that aren’t on the actual chat but
that’s okay that’s what you get for having the the yeah being in control right um a lot of our kiddos
I you know end up on risperidone which I think for us that certainly helped but I think we still have
a long ways to go in terms of improving things and I’m just wondering what we could take to our
uh neurologists psychiatrists to kind of maybe heighten their awareness on um you know possible
Catatonia because I certainly see you know based seeing my son some of the symptoms that you’ve
uh referred to yeah I think that you know giving them literature on it um we’re trying to publish
as quickly as we can um to try to bring awareness and do talks like this to and you
know for families but also for psychiatrists to say hey look this is something worthy of consideration risperidone and Eric pepper result certainly have their place they’re the only two
FDA approved medications for autism ever and they’re only approved for irritability and
autism there’s no FDA approved treatments for the sort of core features of autism social emotional
relatedness difficulties and restricted interests repetitive behaviors and so you know we’ve done
psychopharmacology research and autism for decades now you know we’ve had a lot of failed clinical
trials and there’s a lot of reasons for that I think that part of it is that there’s a lot of
um heterogeneity in terms of what’s causing autism symptoms like in syngap the autistic
symptoms are probably due to sync app right like it’s probably due to the genetic alteration and the same is true in felon McDermott syndrome but for folks that have autism without an identifiable
genetic abnormality do they have one that we haven’t caught do they have one that we don’t know how to characterize or do they just not have one and so I think part of the challenge there and
one of the reasons why Catatonia in particular is interesting to me from a clinical perspective and research perspective is it something that we’ve described as happening across a myriad of
different neurodevelopmental conditions and it’s something we can treat and so what I would say is if you’re talking to your neurologist or your provider saying like we’ve seen this Behavior
change over the past couple months or something is this something that would be on the you know differential of things we could consider for why this is happening and you’re more than welcome
to give them my contact info and I can share some of our research and data with them too um but I think that a lot of times when you’re talking to Providers bringing up Catatonia if
there is an acute worsening I think is is a really key component because Catatonia really is like
catatoni is not a uh whoa we don’t think Catatonia has a chronic condition we think Catatonia is
something that’s like we have an acute Behavior change that we need to treat and for Jaden I think
that that made a lot of sense where like Jackie is you know super diligent around describing Jaden’s
symptoms and saying like look Jaden has these flares of really significant behaviors that last
x amount of time and then she’s back to herself like that sort of episodic nature again adds
more evidence to the fact that it’s hyperactive catatonia yeah they’re a trigger well I feel like
there’s a trigger and it just comes out of nowhere and you start to become in tune about when maybe
it’s about to happen yeah yeah things are back to normal but the hyperplasticity and I know
in medical terms that probably means something different but um my kid as a teen
cannot anxiety will not go anywhere I mean except School very limited places he used to
go everywhere when he was little sometimes with behaviors but now it’s like major aggression towards us if we’re trying to ask him to get out of the car and go and we don’t know if
that’s a prefer just his preferred what he wants to do doesn’t want to do is it
um yeah I can’t I mean and that’s a whole other aspect of behavior but the aggression was if we could control that we’re saying that parents that would be huge yeah and I think that’s you know
one of the reasons that I was so excited to talk to you guys is that I sort of my
the hill that I kind of die on sometimes is that aggression doesn’t happen without cause right like there’s whether it’s external stressors whether it’s Catatonia whether it’s mood like we
need to push the science and literature in a way where we’re thinking about that of like how do we
identify aggression how do we treat aggression how do we get things improved um so yeah and I I can
definitely appreciate that if there was like even a 10 Improvement in aggression on a day-to-day basis so that would be I would expect life altering for a family yes absolutely thank you
um and I know we have some more questions in the Q a Jackie and Lauren did you want to take those yes
hey wanted to thank you for doing this because it’s so important and
you know we struggled with this a long time before you came to Vanderbilt and before we had access to a doctor with your caliber understanding of this and um a lot of the things you describe especially
during the period of malignant Catatonia um that was some that was probably the most terrifying
time throughout Jaden’s life for us you know and um she was well documented and she was well cared
for by many specialists under the universe care we ran every test we could think of
um we were you know the blood pressure was through the roof and heart rate and respirations and she
we could barely get 500 calories in our day and yet she was destroying the house and it’s super
high aggressive episodes very dangerous to her and us her providers and despite Rheumatology
and complex care and all of these Physicians trying to figure this out none of us had an
answer so what would you say to other parents who you know are in that kind of situation where maybe
they’re not going to be coming into Vanderbilt with a Dr Smith there um maybe they’re going to
their ER their rural hospital or somewhere else that this is completely unknown to them how can
they get care especially those high level of benzodiazepines to kind of stabilize an acute
episode without the parent sounding crazy you know sure um uh a tall requester Jackie um I think that
I I honestly think that in in communities where there’s not providers that are comfortable with
high dose benzodiaz beans looking for ECT treatment is probably the best thing they can do because a lot of ECT providers are going to recognize malignant Catatonia because they treat
malignant Catatonia in a different setting right like um before I met you all I I attract I treated
malignant Catatonia for a kiddo with Encephalitis at Children’s right and so a lot of these ECT
providers are going to have seen medically ill folks with malignant Catatonia and if
you walk in and you say like hey vital signs are through the roof uh you know they’re not eating
they’re not drinking we feel like this is something in Catatonia a lot of ECT
providers can be able to recognize that part of the challenge there again is that
ECT is a really invasive procedure it’s heavily stigmatized and there’s a not enough providers
in the country to be able to accommodate those needs and so what I would say is you know try
to use these groups try to you know have folks to reach out to or even say like have you heard
of this would you be willing to look into this for me and then even in an ER setting I think it would
be totally reasonable to say hey can you give my kid two milligrams of Ativan and see if they get better you know that’s a that’s a pretty low um bar to say like could we try this pretty you
know innocuous medication that you use all the time to see if we can get significant benefit
um and so that that would be it’s a tough I totally recognize it’s a tough thing um I get a lot of emails from folks with kids of Phil McDermott with the George where they’re
saying like we don’t have anybody in our community that recognizes what’s going on and so we try to hook them up with people and do some education around that and so I’m always happy to try to
facilitate some of those things but I think those would be kind of low-hanging fruit to go for
we have some questions in the the chat box from Alicia Talbot says Down syndrome dysregulation
disorder and or hands the pandas these would potentially respond with these treatments as well
Down syndrome disintegrated disorder yes um there there’s pretty robust literature and
evidence looking at Down syndrome disintegrative disorder is a phenotype or like a subtype of Catatonia it’s uh in Downs there’s like a more chronic onset and it’s oftentimes associated with
um comorbid gastrointestinal disease in autoimmune conditions and so yes ECT can definitely help with
uh with that as can high dose benzodiazepines It’s tricky in Down syndrome though because
folks with Downs because they have the third 21st chromosome are at a significantly elevated risk for Alzheimer’s dementia already and so if they’re getting high dos benzodiaz beans it’s
likely that that’s going to exacerbate the risk but to my mind it’s control the Catatonia first
you know make sure that we’re having like we’re doing well right now because again it acts like seizures and we have no idea what the long-term cognitive outcomes are for somebody
who has untreated Catatonia but I would imagine you want to treat the Catatonia first and then come worry about the second part later and then pans and pandas is um it’s a little it’s a little
bit complicated of an issue because there there’s not a lot of so the short answer is is no is that
um pans and pandas generally those are treated in a similar sort of way as refractory OCD
um which ECT and hydros benzodiaz beans have not been utilized for with like good success
Corey Basin asks what next steps do you recommend for singap one parents
I think um you know if you’re worried about Catatonia for your kiddo
and you have a psychiatrist that you see I think bringing it up with them and showing them the most current literature is a reasonable thing to do you know we
we learn a ton from our patients and their families and you know we should always be sort of open to listening like hey I’ve done my research like my you know phrase is always like
you’re the expert of your own child right like you know when something is off or you know when something’s different and that collaboration with families I think is really important and so I if
you’re worried about it and you think it might be a con a component or condition of what’s going on with your child I would definitely you know bring literature bring it up with your psychiatrist
Minnie’s I’ll ask a good question I’ve asked you this before myself um so as far as ECP ECP
protocols do they have to do ECP for a specific period of time um does catatonic conditions
come back over time and people have to get a series of ECT again how long does that go on
uh we’re still trying to figure that out um in the paper that we put out last year where we looked at
10 years of data some folks responded and never had to have maintenance treatment so they so the
classic traditional way that folks do it is they come in they get three ECT treatments a week for
four weeks and then they start spacing them out where they’ll get one a week and then one every other week and then one monthly and then eventually stop and then for the majority of
folks that does the trick where it’s like okay you know we don’t need to do continuous maintenance treatment we have had folks with really severe cases where they’ve come in weekly for a long
time for control for symptom control and so it’s it’s very sort of person-to-person dependent
um but for those folks that come in weekly it’s usually it’s usually a life-saving intervention
where without it they are not eating or they’re having really significant Vital sign instability
and whatnot foreign yeah I specifically like that you pointed out that um genetic disorders
are often excluded from the research and even when we are researching conditions such as cavitonia
um I think that that’s really affecting the ability for us to get treatments and so
um it’s definitely something for us to consider yeah absolutely
well I really appreciate you guys inviting me this is great and I’m happy to come back in the future or talk more about cat Tony or cool absolutely thank you very Dr Smith
this was very informative of course yeah it was a pleasure okay take care take care bye